Project Summary: Experience and activity profoundly impact the refinement of synaptic connections among neocortical neurons and are particularly important during sensitive developmental periods. For example, visual deprivation decreases visual acuity (amblyopia) and cortical responsiveness to visual stimulation, but only during a brief window of time during development, the "critical period" for visual cortical plasticity. Though plasticity of excitatory synapses has been extensively studied, plasticity at inhibitory synapses and how it relates to experience-dependent changes in visual cortex remain largely neglected. Inhibition critically regulates information processing within neocortical microcircuits and controls the output of excitatory principal cells. This proposal outlines experiments that address activity-dependent regulation of inhibitory synapses in primary visual cortex, with a special interest in how plasticity at these synapses may relate to the formation and modulation of lateral inhibition in primary visual cortical microcircuits. This proposal also details experiments to study the influence of postsynaptic calcium in the induction and suppression of inhibitory synaptic plasticity, as an important first step to understanding the pathways that lead to increased inhibitory synaptic strength. As with plasticity at excitatory synapses, inhibitory synaptic plasticity likely evolves during the course of development. The present proposal investigates whether the opening of the critical period for visual cortical plasticity is accompanied by changes in the activity-dependent regulation of inhibition. These questions will be pursued using quadruple whole-cell current- and voltage-clamp recording of fast-spiking inhibitory interneurons and excitatory star pyramidal cells in acute slices containing layer 4 mouse primary visual cortex. Together, the experiments proposed will significantly expand our understanding of how and when activity modifies inhibitory synapses in developing visual cortical microcircuits and will address the role of activity-dependent plasticity of inhibition in the timing of the critical period for plasticity in primary visual cortex. Relevance: Visual deprivation potentiates inhibitory synapses in primary visual cortex during the critical period, suggesting that inhibitory synaptic plasticity is a potential mechanism underlying certain visual dysfunctions that arise early in development, such as amblyopia. This proposal aims to examine inhibitory synaptic plasticity in detail, potentially illuminating a link to visual impairments such as amblyopia. Furthermore, these studies may provide insight into the pathological processes that underlie a number of neurological disorders that have been linked to inhibitory dysfunction, including epilepsy, schizophrenia, and autism. [unreadable] [unreadable] [unreadable]